The present invention relates generally to a method for forming an endovascular occlusion to treat conditions such as arteriovenous malformations, aneurysms, excessive blood supplied to tumors, control of massive vascular hemorrhaging, and other conditions which require an embolization to alleviate the condition. More particularly, the present invention relates to a method for forming an endovascular occlusion using calcium alginate by controlling the injections of a purified alginate liquid and a calcium chloride solution to meet and polymerize at a site within the vascular system targeted for occlusion.
Endovascular polymer treatment is a new and growing field for achieving vascular occlusion of blood flow. With this technique, polymer materials are injected directly into blood vessels so that the polymer material will travel to the targeted site in the vascular system and polymerize to form an endovascular occlusion at the target site. Current endovascular embolizations use materials such as isobutyl-2-cyanoacrylate (IBCA), poly vinyl alcohol (PVA), ethanol, polylene threads, hyaluronic acid gels, and cellulose acetate to treat vascular defects such as arteriovenous malformations (AVMs) and aneurysms.
Many polymer materials used for endovascular embolization are toxic and typically require organic solvents that can damage and weaken blood vessel walls. Some endovascular polymer xe2x80x9cgluesxe2x80x9d adhere to the vessel by damaging and infiltrating the wall of the blood vessel, thereby increasing the likelihood of hemorrhage. In addition, current polymer glues are difficult to control which results in the polymer gluing the inside of the delivery catheter and sometimes gluing the catheter to the blood vessel wall.
Calcium alginate is a two component polymer that exhibits high mechanical strength in its stable solid form and low viscosity in its injectable liquid form. This polymer consists of a natural polysaccharide gel component, alginic acid, which is derived from brown algae and is instantly cross-linked when contacted with calcium chloride to form calcium alginate. Alginate has many uses in bioengineering and can be used in polymer films, cell encapsulation, wound dressings, and surgical sponges, to name just a few. For example, U.S. Pat. No. 5,650,116 discloses a method for making medical devices such as stents, catheters, cannulas, plugs and constrictors from alginic acid, among other ionically cross-linkable polymers, and the crosslinking cation calcium. The cross-linkable polymer is introduced through a die to form a tube while the cross-linking ion in solution is simultaneously pumped through the formed tube. The formed tube is extruded from the die into a crosslinking ion solution to cross-link the formed tube which is used to make a stent, catheter, or cannula.
Calcium alginate may also be used as a vascular occlusion agent that is injected into a blood vessel for travel to a targeted site in the vascular system. For example, U.S. Pat. No. 5,614,204 describes angiographic vascular occlusion agents and a method for hemostatic occlusion. A liquid biopolymer gel in situ in contact with divalent cations is one example of a vascular occlusion agent that is described. The mode of administration includes dissolving the biopolymer in a solution that does not cause it to gel and injecting the bipolymer in liquid form to the site where the occlusion is needed. A calcium solution is independently added before, during or after the injection of the biopolymer. However, this mode can still result in either early polymerization or failure to occlude the targeted area. Other modes of administration include injecting a biopolymer solution and allowing it to act with calcium ions in the blood, combining the biopolymer with platelet-rich plasma and injecting it into a vessel, and ejecting a bipolymer solution from a catheter and dropping it into a calcium chloride solution followed by injecting the resulting solution through a catheter to the bleeding area. The same risks may also exist with these modes of administration.
Certain forms of alginate are considered biocompatible because of their natural polysaccharide structure. Alginate gels have an extremely high water content thereby allowing diffusion of the reactive component, calcium chloride, and biological fluids into the polymer. The reactive component calcium chloride is also considered biocompatible at certain dosages. Accordingly, although calcium alginate has previously been identified as an endovascular occlusion agent, there is a need for a method of administration which enables control of the occlusion agent to meet and polymerize at the target site.
The present invention is directed to a new and flexible treatment option for endovascular occlusion that optimizes alginate with various microcatheter delivery systems. Calcium alginate, which is a biocompatible and mechanically stable, embolizing two component polymer, is selectively delivered to blood vessels from microcatheters to perform effective endovascular polymer occlusion. In one embodiment of the invention, separate polymer components are introduced from separate blood vessels and from opposite directions and are controlled to meet and polymerize at a specified point within the vascular system.
In another embodiment of the invention, separate polymer components are simultaneously introduced into the same blood vessel by a dual-lumen microcatheter and are controlled to meet and polymerize at the target site within the vascular system.
In yet another embodiment of the invention, staged injections of the separate polymer components may be controlled to meet and polymerize at a specified point within the vascular system.
One aspect of the invention involves utilizing a two-component polymer comprising a purified alginate having a high guluronic acid content. The alginate is purified by the following steps: 1) the alginate is dissolved in a chelant in an ice bath and the resulting solution is filtered through syringe filters, 2) the solution is placed in an ice bath and its pH is lowered to 3 to form an alginate precipitate, 3) the solution is filtered and the liquid is discarded, 4) a mixture of chloroform and butanol is added to the alginate precipitate and stirred for a predetermined time period to remove proteins interacting with the alginate, 5) the solution is filtered and the liquid is discarded, 6) the alginate precipitate is re-dissolved in deionized water and its pH is increased to 7 over a predetermined time period, 7) another chloroform and butanol mixture is added to the solution and stirred for a predetermined amount of time to remove remaining proteins, 8) the solution is then centrifuged to separate the water and alginate solution from the chloroform and protein solution and precipitated protein contaminants, 9) the top layer of water and alginate solution is aspirated off and ethanol is added to it to precipitate the purified alginate, 10) the purified alginate is filtered and dried, and 11) the purified alginate is sterilized with ethylene oxide.
In another aspect of the invention, the purified alginate is used to make a purified alginate solution where the purified alginate has a concentration of less than 3%. The purified alginate may be mixed with water or a solution comprised of water and radiological contrast agent to form the purified alginate solution. The purified alginate solution has physical characteristics which include low viscosity, high polymer yield, and high mechanical stability.
The viscosity of the unreacted purified alginate solution is preferably within a range of about 25 cP to 275 cP. The reacted purified alginate solution comprises a polymer yield within a range of about 25% to 75% and a mechanical stability within a range of about 14 kPa to 30 kPa with respect to 40% compression.
Another aspect of the invention includes a calcium chloride solution, acting as a crosslinking ion, having a calcium chloride concentration in the range of about 5% to 12%. The calcium chloride solution may be formed by dissolving calcium chloride in water or a solution comprised of water and radiological contrast agent.
The calcium alginate is optimized for forming an endovascular occlusion by controlling the injection rate, injection pressure, and viscosity of the purified alginate solution and the calcium chloride solution. Predetermined injection rates, injection pressures and viscosities for the two solutions are determined by the length, diameter, and surface area of the microcatheters that are used for injection after evaluating characteristics of the blood flow through the blood vessels in the targeted area.